CARDIOVASCULAR AND RESPIRATORY EFFECTS OF ENDOTHELIN IN THE VENTROLATERAL MEDULLA OF THE NORMOTENSIVE RAT

We studied the relevance of the ventrolateral medulla for the cardiova scular and respiratory effects of endothelin-1 in urethane-anesthetize d rats. Microinjection of endothelin-1 into the rostral ventrolateral medulla (RVLM) evoked presser and bradycardic effects followed by sust ained decreases in blood pressure, bradycardia, and respiratory depres sion. These effects were inhibited by endothelin-A receptor antagonist s (BQ-123 and BQ-610) but not by endothelin-B antagonists. In the caud al ventrolateral medulla (CVLM) endothelin-1 decreased blood pressure, renal sympathetic nerve activity, respiratory frequency, and phrenic nerve activity, whereas heart rate increased. Pretreatment. with BQ-12 3 in the CVLM increased respiratory frequency by 15+/-6 breaths per mi nute and prevented the effects of intra-CVLM administration of endothe lin-1. In separate experiments, the intracisternal administration of e ndothelin-1 (20 pmol) to rats pretreated with saline in both the RVLM and CVLM resulted in a hypotensive and bradycardic phase that was foll owed by hyper tension (50+/-15 mm Hg), bradycardia, and 100% mortality . In a separate group, pretreatment with BQ-123 in the RVLM and CVLM c ompletely inhibited the hypotensive phase and reduced by 83% the subse quent rise in blood pressure evoked by endothelin-1. Cardiorespiratory arrest was prevented in all the rats in this group. Selective endothe lin receptor blockade in the RVLM attenuated the hypertensive period o f intracisternal administration of endothelin-1 and prevented mortalit y by 33%, whereas in the CVLM the endothelin receptor antagonist inhib ited the initial hypotension and reduced mortality by 25%. Our results support the concept that in the ventral medulla, endothelin-1 can mod ulate cardiovascular and respiratory function.